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(Stroke. 1995;26:1471-1477.)
© 1995 American Heart Association, Inc.
Articles |
Oral Anticoagulants and Intracranial Hemorrhage
Facts and Hypotheses
From the Department of Medicine (Neurology), University of Texas Health Science Center, San Antonio (R.G.H., B.S.B.), and the Department of Neurology, University of Minnesota, Minneapolis (D.C.A.).
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Abstract |
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 Top Abstract IntroductionICH in Anticoagulated PatientsSubdural Hematoma in...OACs for Stroke Prevention:...References |
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Background Intracranial hemorrhage is the most feared and lethal complication of oral anticoagulation. We review the frequency, predictors, and prognosis of this most common neurological complication of oral anticoagulation.
Summary of Review Anticoagulation to conventional intensities increases the risk of intracranial hemorrhage 7- to 10-fold, to an absolute rate of nearly 1%/y for many stroke-prone patients. Most (70%) anticoagulant-related intracranial hemorrhages are intracerebral hematomas (approximately 60% are fatal); the bulk of the remainder are subdural hematomas. Predictors of anticoagulant-related intracerebral hematoma are advanced patient age, prior ischemic stroke, hypertension, and intensity of anticoagulation. In approximately half of anticoagulated patients with intracerebral hematoma the bleeding evolves slowly over 12 to 24 hours, and emergency reversal of anticoagulation is crucial.
Conclusions Both patient factors and anticoagulation intensity importantly influence the rate of anticoagulation-related intracranial hemorrhage. Patient-related risk factors for this complication overlap with those for ischemic stroke. The risk/benefit equation of anticoagulation for elderly, stroke-prone patients is complex and differs from that for younger patients. The absolute rate reduction (not the relative risk reduction) of ischemic stroke by anticoagulation is the critical issue and must offset accentuation of often lethal brain hemorrhage.
Key Words: anticoagulants • cerebral hemorrhage • intracerebral hemorrhage
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Introduction |
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TopAbstractIntroductionICH in Anticoagulated PatientsSubdural Hematoma in...OACs for Stroke Prevention:...References |
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Intracranial hemorrhage is the most serious and lethal complication of oral anticoagulants (OACs).1 2 3 As hundreds of thousands of elderly patients are now receiving OACs for recently validated indications,4 5 6 the frequency of OAC-associated intracranial hemorrhage is likely to increase. In certain patient populations the occurrence of intracranial hemorrhage has been reported to negate the reduction in ischemic stroke by OACs.7 Hence, intracranial hemorrhage is often a major clinical concern about anticoagulation of elderly patients for stroke prevention. We review current concepts regarding the frequency, predictors, and treatment of OAC-related intracranial hemorrhage.
Intracranial hemorrhages associated with OACs can be divided into intracerebral (more accurately, intraparenchymal), subdural/epidural, and subarachnoid. Before the advent of CT, subdural hematoma was usually considered more common than intracerebral hemorrhage (ICH) in patients receiving OACs.8 9 10 11 12 In recent studies ICHs constitute approximately 70% of OAC-associated intracranial hemorrhages, while subdural hematomas compose the bulk of the remainder.1 8 13 14 15 Simultaneous ICH and subdural hematoma can occur in anticoagulated patients.16
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ICH in Anticoagulated Patients |
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TopAbstractIntroductionICH in Anticoagulated PatientsSubdural Hematoma in...OACs for Stroke Prevention:...References |
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ICH is the most common and least treatable neurological complication of OACs in the elderly.1 2 Conventional intensities of anticoagulation (international normalized ratio [INR], 2.5 to 4.5) increase the risk of ICH 7- to 10-fold.6 15 17 18 19 20 The mortality of OAC-associated ICH is approximately 60% (range, 46% to 68%), making these strokes far more lethal than brain infarction (Table 1
). While
overrepresentation of the cerebellum in OAC-related ICH has
been reported,21 aggregate data do not suggest special
involvement of the cerebellum, and the relative frequency of lobar ICH
is similar in anticoagulated and nonanticoagulated patients (Table 1).
ICHs are immediately visible on CTs; in anticoagulated patients an
almost unique fluid-blood interface can be seen within the first 12
hours as a result of uncongealed blood (Fig 1).25 26 27
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The onset of unusual headache, nausea and vomiting, confusion,
ataxia, or dizziness in elderly patients receiving OACs warrants urgent
evaluation for ICH. In patients taking OACs, approximately 40% of
strokes are ICHs.1 5 6 14 19 Importantly, in
OAC-associated ICH the bleeding evolves slowly, for 24 hours or more,
in perhaps half of patients.1 21 23 24 This is in contrast
to spontaneous ICH in patients who are not anticoagulated, in whom the
duration of bleeding is usually brief (approximately 10% show
progressive enlargement in the first 24 hours28 29 ).
OAC-associated ICHs often continue to enlarge after the diagnosis is
made by neuroimaging studies (Fig 2). This is not
appreciated by many physicians, and reversal of anticoagulation is
undertaken casually, over hours, as the patient deteriorates. Minutes
may well count in OAC-associated ICH. Infusion of prothrombin complex
concentrate appears to reverse the coagulopathy more rapidly than fresh
frozen plasma and was associated with improved outcome in one small
study.23 The role of surgical therapy in lobar and
cerebellar hematoma is uncertain, but given the high mortality,
surgical evacuation may be worth considering.
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In summary, there are two distinct temporal profiles of OAC-associated ICH: those that present with rapidly evolving neurological deficits proceeding to stupor and coma with a high mortality and those (approximately half) that evolve over 6 to 24 hours. This latter group offers the potential for urgent reversal of anticoagulation to minimize morbidity. Further studies to define optimal management are needed.
The mechanism(s) by which OACs accentuate the rate of ICH is
unclear. It seems unlikely, given current concepts, that OACs induce
vascular injury or inhibit vascular repair processes, leading to brain
hemorrhage. OACs (and other antithrombotic agents) may cause
spontaneous subclinical brain hemorrhages to grow to clinical
importance. Small collections of hemosiderin are often
found in elderly hypertensive patients at postmortem in relation to
degenerative small-vessel vasculopathies (Fig 3).30 31 Pathological evidence suggests
that bleeds from smaller or lower pressure vessels than those leading
to massive spontaneous hemorrhages are successfully stanched by
normal hemostatic mechanisms. Hypothetically, under the influence of
antithrombotic agents these small hemorrhages could enlarge. We
speculate that CT or MRI findings of diffuse white matter abnormalities
("leukoaraiosis") may be a predictor of OAC-associated ICH, as
these lesions are related to subcortical vasculopathy in elderly
patients.32
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It is also unclear what immediately precipitates OAC-associated
ICH in most patients (Table 2). Immediate precipitants
could be as trivial as an interval of relatively higher blood pressure
or minor mechanical stress such as the shear forces of vigorous head
shaking. Inciting agents could have differing potency depending on the
nature and intracranial location of the vasculopathy. Clinically
identified precipitants such as minor head trauma, heavy alcohol
intoxication, or acutely elevated blood pressure (induced, for example,
by dental work or extreme cold exposure) are uncommon in OAC-related
ICH in our experience. Severe migraine attacks can rarely precipitate
ICH, but this has not been reported in elderly patients receiving OACs.
Multiple simultaneous ICHs can occur in excessively
anticoagulated patients.
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The inherent risk of ICH in nonanticoagulated patients is
strongly related to patient age and hypertension. The rate of ICH in
patients given OACs has been hypothesized to be this inherent risk
multiplied by a factor determined by intensity of
anticoagulation.17 Patient factors associated with
increased risk of OAC-related ICH have been identified (Table 2
) and
are consistent with this hypothesis. In patients with prior
stroke who experience OAC-associated ICH, bleeding is usually not into
the area of previous infarction. Some have argued that the risk of
OAC-associated ICH is not related to the intensity of anticoagulation
("an all-or-nothing phenomenon with a low
threshold"15 ). Randomized comparisons of ICH risk with
different anticoagulation intensities are limited to four small studies
involving relatively young patients and few ICHs (two ICHs versus no
ICH with higher versus lower intensities,
respectively).36 37 38 39 However, it is increasingly clear that
the relative and absolute risks of OAC-associated ICH are proportional
to the intensity of anticoagulation.2 13 17 21 There is no
absolutely "safe" INR; many patients given OACs experience ICH
with the INR well within the conventionally therapeutic
range.1 14 15
Thus, both patient factors and anticoagulation intensity are
crucial determinants of the absolute rate of ICH. While conventional
intensities of anticoagulation increase the risk of ICH by 7- to
10-fold, the quantitative relationship between intensity and ICH risk
has not precisely been fully defined.13 The absolute rate
of OAC-related ICH for specific patient groups is difficult to predict
accurately, representing a complex interaction of several
patient factors with anticoagulation intensity. In most clinical
reports of patients older than 60 years treated with conventional
intensities of anticoagulation, the absolute rate of intracranial
hemorrhage is between 0.3%/y and 1.0%/y (Table 3). The clinically important variation in the absolute
rate of ICH reported in elderly patients given similar intensities of
OACs is best explained by different inherent risks of spontaneous ICH,
in our view.55 56 Absolute rates of ICH in clinical trials
are probably lower than can be achieved in general clinical practice in
most circumstances.57
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The combination of OACs with antiplatelet therapy has received considerable recent attention, particularly the combination of low-intensity anticoagulation with aspirin.53 58 Aspirin appears to double the risk for ICH, regardless of the dose.59 The combination of aspirin with warfarin probably increases the risk for ICH over similar intensities of anticoagulation without aspirin (pooled data from four randomized trials of OACs show 15 ICHs with aspirin 100 to 1000 mg/d versus 7 without aspirin).53 54 60 61
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Subdural Hematoma in Anticoagulated Patients |
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TopAbstractIntroductionICH in Anticoagulated PatientsSubdural Hematoma in...OACs for Stroke Prevention:...References |
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Subdural hematomas are less frequently reported than ICH in patients receiving OACs, but they are crucial to recognize because they are life-threatening and amenable to surgical therapy. OACs increase the risk of subdural hematoma 4- to 15-fold.8 62 The rate of OAC-associated subdural hematoma is related to the intensity of anticoagulation,13 62 advanced patient age,13 and perhaps cerebral atrophy. In contrast to OAC-related ICH, hypertension does not appear to be associated with OAC-associated subdural hematoma, and precipitation by minor head trauma is notable.8 The absolute rate of subdural hematoma can be estimated as approximately 0.2%/y in elderly patients given OACs (INR
3). Headache and mental status changes are prominent early symptoms, which can evolve for days to weeks. Approximately 20% are bilateral. The mortality of OAC-associated subdural hematoma in recent series was 13% to 20%.8 13 Reversal of anticoagulation and surgical drainage are usually undertaken; it is unclear whether small subdural hematomas causing minimal symptoms in patients receiving OACs can be safely managed nonsurgically, with reversal of anticoagulation.8
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OACs for Stroke Prevention: A Tenuous Balance of Benefit With ICH Risk |
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TopAbstractIntroductionICH in Anticoagulated PatientsSubdural Hematoma in...OACs for Stroke Prevention:...References |
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While the efficacy of antithrombotic therapies is often expressed in terms of relative risk reduction, absolute risk reduction is of the utmost importance. Relative risk reduction is more generalizable between patient subgroups since absolute risk reduction can be difficult to accurately estimate in specific patient subgroups because combinations of comorbid factors influence the absolute rate of events. However, absolute risk reduction is the most important determinant of benefit.63 For example, among unselected survivors of myocardial infarction, OACs (INR, 2.7 to 4.8) reduce the long-term rate of ischemic stroke by an impressive 6%, but the absolute rate reduction is only approximately 1%/y (Table 4
). In these patients OACs increase the rate of
intracranial bleeding 10-fold, to approximately
0.4%/y.5 6 19 So while OACs effectively lower the rate of
ischemic stroke by approximately 1%/y, they increase the rate
of more severe hemorrhagic stroke by approximately 0.4%/y, and the net
benefit to the brain is minimal for unselected survivors of myocardial
infarction anticoagulated to these intensities (the effect on vascular
death and other morbidities must also be considered in the risk/benefit
equation). Specific subsets of patients with prior myocardial
infarction (eg, those with left ventricular thrombus or
atrial fibrillation) with a higher risk for ischemic stroke may
benefit from OACs.
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Accurate estimates of absolute risk reduction by anticoagulation are
thus critical for the optimal clinical application of OACs for stroke
prevention. Ideal candidates for OACs are hypothetically patients with
a high rate of ischemic stroke, substantially reduced by OACs,
who have a low inherent risk of ICH. Unfortunately, risk factors for
ischemic stroke and ICH overlap in many patients (eg, advanced
age, hypertension, prior stroke). Patients who are elderly (aged >70
years) with hypertension have an inherent risk for ICH that is
multiplied by OACs to absolute rates approaching 1%/y (Table 5). Lowering the target intensity (INR, 1.5 to 2.5) may
be sensible for patients at high risk for ICH, although the efficacy of
this range has not been established for stroke prevention and
characterization of patients at high risk for ICH is incomplete.
Whether and how lower intensities of anticoagulation (INR, <2.5), with
or without aspirin, will shift the risk/benefit equation for stroke
prevention is not presently clear and of obvious clinical
importance.
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Footnotes |
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Reprint requests to Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX 78284-7883.
Received March 27, 1995; revision received May 1, 1995; accepted May 1, 1995.
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M. H. Eckman, J. Rosand, K. A. Knudsen, D. E. Singer, and S. M. Greenberg Can Patients Be Anticoagulated After Intracerebral Hemorrhage?: A Decision Analysis Stroke, July 1, 2003; 34(7): 1710 - 1716. [Abstract] [Full Text] [PDF]
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S. P. Johnsen, L. Pedersen, S. Friis, W. J. Blot, J. K. McLaughlin, J. H. Olsen, and H. T. Sorensen Nonaspirin Nonsteroidal Anti-Inflammatory Drugs and Risk of Hospitalization for Intracerebral Hemorrhage: A Population-Based Case-Control Study Stroke, February 1, 2003; 34(2): 387 - 391. [Abstract] [Full Text] [PDF]
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